CTTI Releases 2015 Annual Report


The Clinical Trials Transformation Initiative (CTTI) has released its Annual Report for 2015. The report describes major achievements from the previous year, including new recommendations and related tools and checklists for improving the safety, efficiency, and overall quality of clinical research.

Cover page of CTTI Annual Report with embedded link to CTTI webpage containing report.
2015 CTTI Annual Report

Highlights of the 2015 Annual Report include recommendations on topics including:

  • Ethics review processes
  • Good Clinical Practice training for trial investigators
  • Research protocol design
  • Engagement of patient groups as equal partners in clinical research
  • Informed consent processes
  • Safety reporting systems for research participants

A public-private partnership whose many stakeholders include government agencies, advocacy groups, professional societies, academic research organizations, and representatives from the medical products industry, CTTI’s mission is to “identify and promote practices that will increase the quality and efficiency of clinical trials.”

A PDF version of the report is available here. Previous Annual Reports are also available on the CTTI website.


 

Recent Collaboratory Publications on Research Ethics


The American Journal of Bioethics has recently published three articles authored by members of the Regulatory/Ethics core group describing various questions related to research on medical practices:

  • Is shared decision making an appropriate analytic frame for research on medical practices (Sugarman 2015) discusses the role of shared decision making (SDM) in research on medical practices. The author cautions that “while SDM is in many ways similar to informed consent, there are some important differences, especially in the research setting.” This publication is freely accessible through PubMed Central.
  • Patients’ views concerning research on medical practices: implications for consent (Weinfurt et al. 2015) describes the results of focus group sessions that elicited a range of patients’ views and opinions about different types of research on usual medical practices. The authors state that “our data suggest that effective policy and guidance will involve balancing different patients’ interests and potentially different sets of interests for different types of research studies on usual medical practices.”
  • Ethics of research in usual care settings: data on point (Sugarman 2016) introduces a special five-article supplement in the American Journal of Bioethics, stating that the “growing empirical ethics literature regarding research in usual care settings provides data to inform conceptual and policy debates regarding this research and suggests areas that require further study.”

These publications were supported by a bioethics supplement awarded to the Regulatory/Ethics Core group by the NIH’s Office of the Director.


CTSA-PCORnet Webinar: A Central IRB Approach


The webinar copresented on March 2, 2016, by the Clinical and Translational Science Awards (CTSA) program and PCORnet is available as a video and slideset.

Petra Kaufmann, MD, MSc
Director, Office of Rare Diseases Research and Division of Clinical Innovation
National Center for Advancing Translational Sciences
National Institutes of Health

Rachael Fleurence, PhD
Program Director, CER Methods and Infrastructure Program
Patient-Centered Outcomes Research Institute

Sabune J. Winkler, JD
Director, Regulatory Affairs Operations
Harvard Catalyst

Webinar details:
March 2, 2016
3pm - 4pm ET
To join the WebEx, click here: http://bit.ly/1TGRTFS
Call-in number: 1-855-244-8681
Access code: 737 807 582

Upcoming CTTI Webinar on Informed Consent Recommendations


CTTI-logo-127x100The Clinical Trials Transformation Initiative’s Informed Consent Project will unveil recommendations and associated resources for informed consent on Thursday, November 19.

Presenters include Jennifer Lentz, Global Informed Consent Process Owner in Global Clinical Operations at Eli Lilly and Company, and Michele Kennett, Assistant Vice Chancellor for Research and Director of the Institutional Review Board at the University of Missouri.

Topic: Informed Consent Project Recommendations
• Date: Thursday, November 19, 2015
• Time: 12 – 1 pm EST

To join the public webinar:
 
Meeting Number: 732 884 847 
Meeting Password: ctti 

After you connect to the website, please follow step-by-step instructions for connecting to the audio. If you prefer to connect to audio only, you can join by phone at:

1-855-244-8681 Call-in toll-free number (US/Canada) 
1-650-479-3207 Call-in toll number (US/Canada)

Modernizing the Common Rule for the 21st Century


The New England Journal of Medicine today published a perspective by NIH Deputy Directory Kathy L. Hudson, PhD, and NIH Director Francis S. Collins, MD, PhD, in which they outline the major reforms proposed for regulations governing the ethical conduct of research involving humans, known as the Common Rule (45 CFR 46, Subpart A).

The proposed changes are meant to enhance respect for research participants, calibrate oversight to level of risk, simplify consent documents, streamline IRB review, increase privacy and security safeguards, and facilitate broad participation in research.

“These long-overdue reforms will bring the Common Rule into the 21st century. They should help the scientific community take a giant leap forward in showing respect for research participants, without whom the biomedical research enterprise would cease to exist.”

The NIH is encouraging all stakeholders—the public, researchers, and patients—to closely review the proposed changes and participate in the comment process by the December 7, 2015, deadline.

For more information on the proposed revisions:

Grand Rounds Presentation, Kathy Hudson (video)

Department of Health and Human Services' website on the NPRM 

OHRP Webinars on the NPRM

Living Textbook Chapter: Informed Consent: Emerging Issues and Controversies

OHRP Town Hall Meeting to Discuss NPRM


The Office for Human Research Protections (OHRP) has announced a public Town Hall Meeting to be held October 20, 2015, to respond to questions related to the Federal Policy for the Protection of Human Subjects Notice of Proposed Rulemaking (NPRM) published on September 8, 2015.

The goal of the NPRM is to modernize, strengthen, and make more effective the Federal Policy for the Protection of Human Subjects that was promulgated as a Common Rule in 1991. The NPRM seeks comments on proposals to better protect human subjects involved in research, while facilitating valuable research and reducing burden, delay, and ambiguity for investigators.

The purpose of the Town Hall Meeting (agenda) is for OHRP, HHS agencies, and other Common Rule departments and agencies to provide responses to questions from the public about the NPRM in order to clarify the NPRM proposals and better inform public comment on the NPRM. The public will be able to ask questions during the Town Hall Meeting, and to submit questions before the meeting. Watch via webinar.

Public Town Hall Meeting 
October 20, 2015, 9 am to 5 pm
Hubert H. Humphrey Building, Great Hall
200 Independence Ave SW
Washington, DC 20201

This PDF document (#2015-25564) contains details about the format of the public Town Hall Meeting and how to register or submit questions prior to the meeting.

Important deadlines:

  • While there is no registration fee, individuals planning to attend the Town Hall in person must register by 5:00 pm October 13, 2015. Registration will be accepted on a first-come, first-served basis and may be completed by sending an email to OHRP@hhs.gov, with the subject line “Registration for OHRP Town Hall Meeting.”
  • The deadline for submission of questions about the NPRM prior to the Town Hall Meeting must be received no later than 5:00 pm October 13, 2015.
  • Details on the NPRM are at the OHRP website. To be assured consideration, comments on the NPRM must be received no later than the extended deadline of January 6, 2016.

 

Special Issue Published on Ethical & Regulatory Complexities of Pragmatic Clinical Trials


Tools for ResearchA new series of 12 articles published in a special issue of the journal Clinical Trials addresses ethical and regulatory challenges particular to pragmatic clinical research. Pragmatic clinical trials are designed to efficiently provide answers to important clinical questions, yet they present special challenges in conforming to the ethical and regulatory guidelines that were developed for more traditional clinical research. The special issue describes these challenges and begins to outline possible solutions that will protect the rights and welfare of research participants while allowing pragmatic clinical trials to gather much-needed evidence for informing healthcare decisions. An introductory article is followed by 11 articles addressing individual topics, such as alteration of informed consent, privacy, gatekeepers, and defining minimal risk research. The effort was funded by the NIH Health Care Systems Research Collaboratory, with additional support from the Patient-Centered Outcomes Research Institute (PCORI), and involved diverse groups of stakeholders, including researchers, patient advocates, bioethicists, and regulatory experts. Robert M. Califf, MD, and Jeremy Sugarman, MD, MPH, were editors of the special issue.

For more information:


Notice of Proposed Rulemaking (NPRM): Protection of Human Subjects


The U.S. Department of Health and Human Services (HHS) and 15 other federal departments and agencies have announced proposed revisions to modernize, strengthen, and make more effective the Federal Policy for the Protection of Human Subjects that was promulgated as a Common Rule (45 CFR 46, Subpart A)  in 1991. A Notice of Proposed Rulemaking (NPRM) was published in the Federal Register on September 8, 2015 (see the press release).

The NPRM seeks comment on proposals to better protect human subjects involved in research, while facilitating valuable research and reducing burden, delay, and ambiguity for investigators. Comments must be received no later than the extended deadline of 5 pm on January 6, 2016. Visit the HHS page for a summary of the proposed changes and instructions on submitting or browsing comments.

Webinars are available explaining the changes proposed in the NPRM, and a town hall meeting is planned to be held in Washington, DC, in October.

Among the major changes being proposed in order to better protect research subjects and help build public trust are modifications to rules affecting patient informed consent. With regard to informed consent in general (such as consent to participate in a clinical trial), the rules would be significantly tightened to ensure that the process becomes more meaningful. Consent forms in particular would be affected. A common complaint about informed consent forms is that they are often unduly lengthy and cumbersome, with important information often buried and hard to find. Under the proposed changes, such documents would need to be streamlined in ways that provide appropriate details about the research that is most relevant to a person’s decision to participate in the study, such as information a reasonable person would want to know, and present that information in a way that highlights the key information.

The proposed modifications are designed to continue to uphold the ethical principles upon which the Common Rule is based, as applied to the current social, cultural, and technological environment. In brief, the most significant changes proposed in the NPRM include:

  1. Improve informed consent by increasing transparency and by imposing stricter new requirements regarding the information that must be given to prospective subjects.
  2. Generally require informed consent for the use of stored biospecimens in secondary research.
  3. Exclude from coverage under the Common Rule certain categories of activities that should be deemed not to be research, are inherently low risk, or where protections similar to those usually provided by IRB review are separately mandated.
  4. Add additional categories of exempt research to accommodate changes in the scientific landscape and to better calibrate the level of review to the level of risk involved in the research.
  5. Change the conditions and requirements for waiver or alteration of consent such that waiver of consent for research involving biospecimens (regardless of identifiability) will occur only in very rare circumstances.
  6. Mandate that U.S. institutions engaged in cooperative research rely on a single IRB for that portion of the research that takes place within the United States, with certain exceptions.
  7. Eliminate the continuing review requirement for studies that undergo expedited review and for studies that have completed study interventions and are merely analyzing data or involve only observational follow-up in conjunction with standard clinical care.
  8. Extend the scope of the policy to cover all clinical trials, regardless of funding source, conducted at a U.S. institution that receives federal funding for non-exempt human subjects research.

 

FDA Issues Draft Guidance on Use of Electronic Informed Consent (eIC)


On March 9, 2015, the U.S. Food and Drug Administration (FDA) issued draft guidance on the Use of Electronic Informed Consent in Clinical Investigations (document opens as a PDF). In a question-and-answer format, the guidance provides recommendations for investigators, sponsors, and institutional review boards (IRBs) on the use of electronic media and processes to obtain informed consent for FDA-regulated clinical investigations of medical products, including human drug and biological products, and medical devices, and combinations thereof.

Electronic informed consent, or eIC, refers to the use of electronic systems and processes to convey information related to the study and to obtain and document informed consent. Electronic media formats may include text, graphics, audio, video, podcasts, and interactive websites, biological recognition devices, and card readers. Use of electronic systems may allow for rapid notification to study participants of any amendments pertaining to the informed consent, promote timely entry of eIC data into the study database, and allow for timely collection of the informed consent data from remote locations.

The guidance provides answers to these questions:

  • How should the information in the eIC be presented to the subject?
  • How and where may the eIC process be conducted?
  • How and when should questions from subjects be answered?
  • What steps may be taken to facilitate the subject’s understanding of the information being presented?
  • What steps may be taken to ensure that new or additional information is conveyed to the subject during the course of the clinical investigation?
  • Does FDA allow the use of electronic signatures to document eIC?
  • What special considerations should be given to the use of eIC for pediatric studies?
  • Should subjects receive a copy of their eIC and have easy access to the material and information presented to them in their eIC?
  • What steps can be taken to help ensure confidentiality of the information once eIC is obtained?
  • Can HIPAA authorizations for research, which are frequently combined with informed consent documents, be obtained electronically?
  • What are the IRB’s responsibilities in the eIC process?
  • What eIC documentation does FDA require for submission with applications?
  • What steps can be taken to ensure the system archives the documents appropriately?
  • What materials or documents will FDA require during an inspection?

The comment period ends May 7, 2015. Users can submit electronic comments using the docket number HHS-OPHS-2015-0002 at the Federal eRulemaking Portal: http://www.regulations.gov.


Report from NIH Collaboratory Workshop Examines Ethical and Regulatory Challenges for Pragmatic Cluster Randomized Trials

A new article by researchers from the NIH Collaboratory, published online this week in the journal Clinical Trials, explores some of the challenges facing physicians, scientists, and patient groups who are working to develop innovative methods for performing clinical trials. In the article, authors Monique Anderson, MD, Robert Califf, MD, and Jeremy Sugarman, MD, MPH, MA, describe and summarize discussions from a Collaboratory workshop on ethical and regulatory issues relating to pragmatic cluster-randomized trials.


Pragmatic Cluster-Randomized Trials

Many of the clinical trials that evaluate the safety and effectiveness of new therapies do so by assigning individual volunteers to receive either an experimental treatment or a comparator, such as an existing alternative treatment, or a placebo. However, this process can be complex, expensive, and slow to yield results. Further, because these studies often take place in specialized research settings and involve patients who have been carefully screened, there are  concerns that the results gathered from such trials may not be fully applicable to “real-world” patient populations.

For these reasons, some researchers, patients, and patient advocacy groups are interested in exploring different methods for conducting clinical trials, including designs known as pragmatic cluster-randomized trials, or CRTs. In a pragmatic CRT, groups of individuals (such as a clinic, hospital, or even an entire health system) are randomly assigned to receive one of two or more interventions being compared, with a focus on answering questions about therapies in the setting of actual clinical practice—the “pragmatic” part of “pragmatic CRT.”

Pragmatic CRTs have the potential to answer important questions quickly and less expensively, especially in an era in which patient data can be accessed directly from electronic health records. Just as importantly, that knowledge can then be fed back to support a “learning healthcare system” that is constantly improving in its approach to patient care.  However, while cluster-randomized trials are not themselves new, their widespread use in patient-care settings raises a number of potential challenges.

For example: in a typical individually randomized clinical trial, patients are enrolled in a study only after first providing written informed consent. However, in a CRT, the entire hospital may be assigned to provide a given therapy. In such a situation, how should informed consent be handled? How should patients be notified that research is taking place, and that they may be part of it? Will they be able to “opt out” of the research? What will happen to the data collected during their treatment? And what do federal regulations governing clinical trials have to say about this? These are just a few of the questions raised by the use of pragmatic CRTs in patient-care settings.


The NIH Collaboratory Workshop on Pragmatic Cluster-Randomized Trials

The NIH Collaboratory Workshop of Pragmatic CRTs, held in Bethesda, Maryland in July of 2103, convened a panel of experts in clinical trials, research ethics, and regulatory issues to outline the challenges associated with conducting  pragmatic CRTs and to explore ways for better understanding and overcoming them. Over the course of the intensive 1-day workshop, conference participants identified key areas for focused attention. These included issues relating to informed consent, patient privacy, oversight of research activities, insuring the integrity of data gathered during pragmatic CRTs, and special protections for vulnerable patient populations. The article by Anderson and colleagues provides a distillation of discussions that took place at the workshop, as well as noting possible directions for further work.

In the coming months and years, the NIH Collaboratory and its partners, including the National Patient-Centered Clinical Research Network (PCORnet), plan to build on this workshop experience. Together, they hope to explore these issues in greater detail and propose practical steps for moving forward with innovative clinical research methods, while at the same time maintaining robust protections for patients’ rights and well-being.


Jonathan McCall, MS, and Karen Staman, MS, contributed to this post.


Read the full text of the article here:

Anderson ML, Califf RM, Sugarman J. Ethical and regulatory issues of pragmatic cluster randomized trials in contemporary health systems. Clin Trials 2015 [e-Pub ahead of press].
doi:10.1177/1740774515571140 
For further reading:

Tunis SR, Stryer DB, Clancy CM. Practical clinical trials: Increasing the value of clinical research decision making in clinical and health policy. JAMA 2003;290(12):1624-32. PMID:14506122; doi:10.1001/jama.290.12.1624.

The Ottawa Hospital Research Institute Ethical Issues in Cluster Randomized Trials Wiki.

Special Report: Ethical Oversight of Learning Health Systems. Hastings Center Report 2013;43(s1):S2–S44, Si–Sii.

Sugarman J, Califf RM. Ethics and regulatory complexities for pragmatic clinical trials. JAMA 2014;311(23):2381-2. PMID: 24810723; doi: 10.1001/jama.2014.4164.